title: Influenza A exacerbates Staphylococcus aureus pneumonia by attenuating IL-1β production in mice.
abstract: Pneumonia is a leading cause of death worldwide. Staphylococcal aureus can be a cause of severe pneumonia alone or a common pathogen in secondary pneumonia following influenza. Recently, we reported that preceding influenza attenuated the Type 17 pathway, increasing the lung's susceptibility to secondary infection. IL-1β is known to regulate host defense, including playing a role in Th17 polarization. We examined whether IL-1β signaling is required for S. aureus host defense and whether influenza infection impacted S. aureus-induced IL-1β production and subsequent Type 17 pathway activation. Mice were challenged with S. aureus (USA 300), with or without preceding Influenza A/PR/8/34 H1N1 infection. IL-1R1(-/-) mice had significantly higher S. aureus burden, increased mortality, and decreased Type 17 pathway activation following S. aureus challenge. Coinfected mice had significantly decreased IL-1β production versus S. aureus infection alone at early time points following bacterial challenge. Preceding influenza did not attenuate S. aureus-induced inflammasome activation, but there was early suppression of NF-κB activation, suggesting an inhibition of NF-κB-dependent transcription of pro-IL-1β. Furthermore, overexpression of IL-1β in influenza and S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 by S. aureus and improved bacterial clearance. Finally, exogenous IL-1β did not significantly rescue S. aureus host defense during coinfection in IL-17RA(-/-) mice or in mice in which IL-17 and IL-22 activity were blocked. These data reveal a novel mechanism by which Influenza A inhibits S. aureus-induced IL-1β production, resulting in attenuation of Type 17 immunity and increased susceptibility to bacterial infection.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224;
authors.forename: Keven M
authors.initials: KM
authors.lastname: Robinson
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Choi
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McHugh
authors.forename: Sivanarayana
authors.initials: S
authors.lastname: Mandalapu
authors.forename: Richard I
authors.initials: RI
authors.lastname: Enelow
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000235:genetics / Q000276:immunology; D060085:Coinfection / Q000276:immunology / Q000382:microbiology / Q000821:virology; D004789:Enzyme Activation / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011023:Pneumonia, Staphylococcal / Q000276:immunology*; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; D007378:Interleukins; D016328:NF-kappa B; D053573:Receptors, Interleukin-1 Type I; D000097043:Interleukin-22